The neuroleptics such as chlorpromazine, haloperidol and clozapine have been studied primarily in relation to their observed effects on brain dopaminergic systems. Much less effort has been directed at assessing the effects of these compounds on brain serotonin metabolism. There is clear evidence that methiothepin, another neuroleptic, is able to elevate brain 5-hydroxyindole (i.e., serotonin and its major metabolite, 5-hydroxyindoleacetic acid) levels; a finding compatible with compensatory synthesis of serotonin following pre-and/or postsynaptic receptor blockade. Concomitant with these changes, methiothepin also favors the uptake of tryptophan into the brain by stimulating insulin secretion and altering plasma amino acid patterns and plasma tryptophan binding to plasma proteins. These changes may represent a metabolic mechanism by which neuroleptics and other drugs affect brain 5-hydroxyindole synthesis. Ability to stimulate 5-hydroxyindole synthesis can be used as a means of assessing the capacity of known peripheral serotonin receptor antagonists, such as methysergide, cyproheptadine and metergoline to act within the central nervous system. The research is aimed at 1) determining the ability of some neuroleptic drugs and known peripheral serotonin antagonists to alter brain 5-hydroxyindoles; 2) determining peripheral actions of these drugs that may contribute to these changes; and 3) examining the ability of serotoninergic systems to develop tolerance and supersensitivity. BIBLIOGRAPHIC REFERENCES: Jacoby J.H., Mueller, G., Wurtman, R.J. Thyroid State and Brain Monoamine Metabolism. Endocrinology 97 (5), 1332-1335, 1975. Jacoby, J.H., Howd, R.A., Levin, M. and Wurtman, R.J. Mechanisms by which Quipazine, a Putative Serotonin Receptor Antagonist, Alters Brain 5-Hydroxyindole Metabolism. Neuropharmacology 15, 529-534, 1976.